Integration of TGF-beta/Smad and Jagged1/Notch Signalling in Epithelial-To-Mesenchymal Transition

EMBO J. 2004 Mar 10;23(5):1155-65. doi: 10.1038/sj.emboj.7600069. Epub 2004 Feb 19.

Abstract

Epithelial-to-mesenchymal transitions (EMTs) underlie cell plasticity required in embryonic development and frequently observed in advanced carcinogenesis. Transforming growth factor-beta (TGF-beta) induces EMT phenotypes in epithelial cells in vitro and has been associated with EMT in vivo. Here we report that expression of the hairy/enhancer-of-split-related transcriptional repressor Hey1, and the Notch-ligand Jagged1 (Jag1), was induced by TGF-beta at the onset of EMT in epithelial cells from mammary gland, kidney tubules, and epidermis. The HEY1 expression profile was biphasic, consisting of immediate-early Smad3-dependent, Jagged1/Notch-independent activation, followed by delayed, indirect Jagged1/Notch-dependent activation. TGF-beta-induced EMT was blocked by RNA silencing of HEY1 or JAG1, and by chemical inactivation of Notch. The EMT phenotype, biphasic activation of Hey1, and delayed expression of Jag1 were induced by TGF-beta in wild-type, but not in Smad3-deficient, primary mouse kidney tubular epithelial cells. Our findings identify a new mechanism for functional integration of Jagged1/Notch signalling and coordinated activation of the Hey1 transcriptional repressor controlled by TGF-beta/Smad3, and demonstrate functional roles for Smad3, Hey1, and Jagged1/Notch in mediating TGF-beta-induced EMT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Differentiation*
  • Cell Movement
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dogs
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Membrane Proteins / metabolism*
  • Mesoderm / cytology*
  • Mesoderm / metabolism
  • Mice
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Receptors, Notch
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Response Elements / genetics
  • Signal Transduction*
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription, Genetic / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cadherins
  • DNA-Binding Proteins
  • FAT1 protein, human
  • Hairy, HRT1 protein
  • Membrane Proteins
  • Receptors, Notch
  • Repressor Proteins
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • fat1 protein, mouse